Certain 1-acyl-3-undecyl pyrazoles



2,926,170 CERTAIN l-ACYL-S-UNDECYL PYRAZOLESf No Drawing. Application January 13, 1958..., i Serial No. 708,380 1 4 Claims. (Cl. 260-3l0) Our invention relates to l-acyl-3-alkylpyrazoles having the structure FJ-l N in which R is an alkyl radical selected from the group consisting of decyl, undecyl and dodecyl radicals, and R is a member of the group consisting of acetyl and benzoyl radicals, and to a process for making-these compounds. These novel compounds have anticonvulsant properties and are useful in the treatment of epilepsy.

Epilepsy has been defined as a cerebral dysrhythmia which may or may not be accompanied by loss of consciousness and body movements. It is now knovvnthat epileptic convulsions are related to the flow of electricity from neurons of the cerebral cortex. The type of chemical reaction which is responsive for these cerebral neuronal discharges is not known, but generally, convulsions and loss of consciousness are characterized by abnormally fast brain waves. When the patient suffers loss of consciousness and convulsions, the seizures'are referred to as grand mal, a form of major epilepsy. How'- ever, convulsions do not necessarily accompany epilepsy, and in some instances consciousness is not lost; When the patient loses consciousness but convulsions are not observed, the attacks are known as petit mal. Afthird type of epilepsy has been clinically classified as psychomotor epilepsy.

Many drugs are known which reduce or diminish epileptic seizures in man. In general, those drugs which will act as depressants of nervous transmission are effective for this purpose. The hypnotics, such as the barbiturates, are eflfective in doses suflicient to produce anesthesia. vulsants, but must be administered in hypnotic doses. The related hydantoins and oxazolidinediones have also been found to possess anticonvulsant properties. Such drugs, however, interfere to a greater or lesser extent with the normal activities of the patient. I

Itis: most important, that any drug which is used as an anticonvulsant have very low toxicity since the nature of epilepsy requires that the patient use the drug daily and over a long period of time. The ideal anticonvulsant drug should be non-toxic, Well tolerated, long acting, and

devoid of sedative eflects. It is a purpose of this invention to provide a method of reducing or eliminating convulsions in animals and in'. man by administering anticonvulsant compositions.

Our new compositions are useful for veterinary purposes. Efiectiveness' has been found for a variety of animals,

including'dogs,inice,rats, and monkeys. p It is also an object of this invention to provide an efficient"--meth6d'=for making l-acylI derivatives of the 3-alkylpyrazoles.

Phenobarbital is one of the better anticom.

nited. States Pate 2,926,170 Batented Feb. 23,1960

1 anticonvulsant composition in unit'dosage form ,which has a high protective index and is' non-toxic over a long period of time of use.

Still another object of this invention is to provide 1-acy1-3-alkylpyrazole compositions for use in the treatment of epilepsy. i

It has been found that the aforesaid pyrazoles have unexpected and-unobvious properties of great value'in combatting epilepsy. 1 These compositions may take the form of tablets, powders, capsules, or other dosage forms which will be particularly usefulfor oral ingestion. The compositions may take the form of active materials, namely the 1-acyl-3-alkylpyra2oles, admixed with solid diluents and/or tabletting adjuvants such as corn starch, sucrose, lactose, magnesium .stearate, talc, aluminum hydroxide, calcium carbonate gums such as acacia, or the like. Any of the tabletting materials used in pharmaceutical practice may be employed where there is no I istered in that form, Alternatively, the 1-acyl-3-alkylpyrazole may be emulsifiedin a ,liquid in ,which th 1-acyl 3-alky1pyrazole is not soluble;

It has been found that only certain members of the l-acyl-3-alkylpyrazole. series have great -value in combatting epilepsy. Insofar as.is.known, the physiological properties of the l-acyl-3 alkylpyrazoles have not heretofore been investigated; nor have any of, these compounds been applied for therapeutic purposesm Anticonvulsant drugs maybe assayed in the laboratory by the minimum electro-shock method. In this procedure, the drug isadministered-orally to the animals under test. After one .hqur, the animal is subjected to a direct-current stimulus that is approximately equal. to three times the current necessary. to produce maximum seizures. The efiectiveness of various l-acyl-S-alkylpyrazoles as ,anticonvulsants. is summarized. in Table .'-I. this table, 1the fi rst columngives the effective dose-in milligrams: per kilogram required to prevent convulsions in one-half of theganimals subjected to the minimum electro-shock procedure. The second .column. indicates the amount of drug in 'milig'rams per kilogram-that produced neurologicaltoxic symptomsfin one-half of the experimental group. The third'f columnof this table reports the amount, of drug, again in,milligrams per kilogram, that was fatal to fifty percent of the test group. Column four indicatesthe protective index v (N.T.S. -E.D. I and the fifth column gives the therapeutic index 'The l-acyle3-alkylpyrazoles of this invention are prepared by'treating the 3-alkylpyrazole with butyllithium and reacting the N-lithiopyrazole so formed with an acyl halide. I

' ,EXAMPLEI 1-benaoyl 3 dccylpyrazole v "To a cold (0 solution of 5.0 grams (0.024 molefof It is-a further'object-"ofthisinvention to provide" an 3-decylpyrazole in 55 milliliters of dry ether is added 3 with Istirring 39.5-milliliters (0.029 mole) of a 0.731 N solution of n-butyl lithium in pentane. Afterten minutes, a solution of 4.2 grams (0.029 mole) of benzoyl chloride in 25 milliliters of ether is added, dropwise with stirring, over-aperiod of ten-minutes. This react ion mixture: is kept :at 25 forone hour" and then '75 milliliters of 6% aqueous sodium bicarbonate is added and the-mixture is stirred vigorously until the 'odor'of benzoyl'chloride can no longer'be dete'cted. The layers are separated and after the ether layer has-beendried with magnesiumsulfate, the ether s'olution -is evaporated and the residue is distilled to give 6.2 grams' (83%) of 1- benzoyl 3 adecylpyrazole boiling point.1-35- 1*37 at 0.001 mm.) as'a colorless viscous oil. a

EXAMPLEII I-benzoyl 3-dodaylpytdzole To acol'd solutionof :0 grar'ns"( 050212 molelof 3'-do'decylpyraz'ole in f 5 5 milliliterjs'of dry are is added with=stirring 37.'7milliters (0:025'4'mole) er a"0.731 N solution of n-butyl lithiuminipentane After ten miniites, a solution of 3:6"grams"(0.0254"mble) of benzoyl chloride-in 25 milliliters of etherjis added,"dropwi's'e with stirring, overa periodfdf ten minutes. TliifsSr'ea'ction mixture is keptat 25 C. for'one hourfandthen 75 milli- 'liters-of'6% aqueous sodium bicarbonatefiisiaddd and the mixture is stirred vigorously until the odor of benzoyl chloride can no longer be d'etected. The layers are separated and after the ether-layerhas been'driedwith magnesium sulfate, the ethersolution is evaporated .and' the residue is distilled to give 56 grams'of1-benzoyl 3- dodecylpyrazole (boiling point l44 "'l46at0.00lmm.) as a colorless liquid.

v EXAMPLE I11 1 acetyl-3-undecylpyrazole To' 'a" cold (0) solution of 107 grams (0.048 mole) of 3-undecylpyrazole in 110 milliliters of dry ether is added with stirring 60 milliliters (0.053 mole) of a solution of "n-butyl lithium in pentane. After ten minutes a solution of 5.7 grams (0.056mole) of-acetic anhydride. in milliliters of "ether is added, dropwise with stirring, over a periodofttenminutes. 3.025 C. for onefhour and then 150 milliliters of 6% aqueous sodium bicarbonateis added and the mixture is 'stirrcd'vigorously untilthe odor of acetic anhydride can no longer'jbe detected. :The layers are separated. and 'aft'er theether layer has been'dried with magnesium sulfa'te, the 'ethers'olutionis-evaporated and the residue is distilled'to give 8.5 grams of 1-acetyl-3-undecylpyrazole, a low meltingsolid' boiling at 104106 at 0.005 mm. This solid was recrystallizedfrom pentane to give 6.7 grams of colorless granules (melting-point 32-33 C.).

EXAMPLE IV I-chloroacetyl-3-undecylpyrazole To a cold (0) solution'of 10.9 grams (0.045 mole) of S-undecylpyrazole in 110 milliliters of dry ether is added with stirring 70 milliliters (0.061 mole) of a solution of n-butyl lithium in pentane. After ten minutes, a solution of 12 grams (0.098 mole) of chloroacetyl chlo- :ride in 25 milliliters of ether is added-dropwise with stirring, over a period of ten minutes. This reaction'mixture is kept at 25 C. for one hour and-then 150 milliliters of 6% aqueous sodium bicarbonate is added and "the mixture is stirred vigorously until the odor. of chloroacet-yl "chloride can no longer be detected. The layers fare}separated and after "the ether layer has (been "dried with'magnesium' sulfate, the ether solution is evaporated and the residue is distilled to give 13.5 grams of a pale yellow viscous liquid whichboils" at 140-145 at 0.02 mm. This liquid was, dissolved in 10 milliliters of prisms' whichnielted at 33-34? C- This reaction mixtureis kept pentane and chilled at 0, .C. to afford 8.3 grams of white 7 from' the spirito f the invention.

EXAMPLE v 1-benzoyl-3-undecylpyrazole To a cold (0") solution of 10.7 grams (0.048 mole) of 3-undecylpyrazole in 160 milliliters of dry ether is added with stirring 60 milliliters (0.053 mole) of a solution of n-butyl lithium in pentan'e. After ten minutes, a solution of 7.9 grams (0.056 mole) of benzoyl chloride in 10 milliliters of ether is added, dropwise with stirring, over a period of ten minues. This reaction mixture is kept at 25 C. for one hour and then milliliters of 6% aqueous sodium bicarbonate is'added and the mixture isstirred vigorously until the odor of benzoyl chlo ride can no longer bedetected. The layers are separated and after the ether layer has been dried with magnesium sulfate, the ether solutionis evaporated and the residue is distilled to give 13.3 grams l-benzoyl-S-undecylpyrazole (boiling point -145 at 0.002 mm.) as a colorless ,oil.

The percentage of l-acyl-3-alkylpyrazole in-a::pharmaceutical composition for the treatment of epilepsy may be varied. It is necessary that the active ingredient con stitute a portion such that suitable dosage will be obtained. Obviously, several dosage unit forms may be administered at about the-same time. Although a percentage less than 0.1% of active ingredient is eifective, it is preferred to use not less'than 0.l% o'f active agent. The percentage of active agent-may be conveniently 10% or'25% oreveu 50% since activity increases'with the concentration of active -material. Tablets containing from about'25 toabout'50 mg.of the" 1-acyl-3-alkylpyrazole" are" particularly useful. The following'formulations are intended-tobe illustrative only, and may be varied or modified to aconsiderable 'extentwithout departing We do not therefore intend to limit this invention to the specific embodiments herein set-forth.

EXAMPLE v1 G. .ca1eium.earp tei -.s- 0.500 1-acetyl-3eundecylpyrazole. 0.005 Calcium stearate. 0.050

The.1 acetyl 3-undecylpyrazole-is adsorbed onto 10% of theicalcium. carbonate by mixing. The remaining calciumv'carbonate,'=previously granulated With water and -'dried,l'is added-to this pyrazole'mixture. The calcium stearate 'is thenaddedi andafter mixingu'nt'il uniform, the mixture is compressed into tablets.

The ,1sbenzoyl-3-undecylpyrazole.is adsorbed onto 10% of the aluminum hydroxide with mixing. The remainder of rther aluminum hydroxide is then;granulatedwith the vsucrose,.lactose,-and gelatin solution and dried at 50 C. These granules are Ethcn mixed :with "the :pyrazolealuminum hydroxide composition and magnesiumstearate untiLuniform-and compressed into tablets.

EXAMPLE VIII G. Calcium-carbonate 0.250 Lactose Y 0.250 Acacia solution 0.005 1-benzoyl 3-decylpyraz'o1e 0.050 Magnesium stearate 0.005

V The .1-benzoyl-3-decylpyrazole is adsorbed onto 10% of the calcium carbonate with mixing. The remainder of the. calcium carbonate. granulated with :the, lactose. and

acacia solution and dried at 50" C. These granules are then added with the calcium carbonate-pyrazole mixture and mixed until uniform with the magnesium stearate. The resulting product is compressed into tablets.

EXAMPLE IX G. Magnesium trisilicate 0.300 Lactose 0.200 Sodium alginate solution 0.005 l-benzoyl-B-dodecylpyrazole 0.050 Magnesium stearate 0.005

EXAMPLE X G. Aluminum hydroxide 0.300 Sucrose, powdered 0.100 Lactose, powdered 0.100 l-chloroacety1-3-undecylpyrazole 0.050 Magnesium stearate 0.005

The 1-chloroacetyl-3-undecy1pyrazole is adsorbed onto of the aluminum hydroxide with mixing. The remainder of the aluminum hydroxide, together with the sucrose and lactose, is then added and the composition mixed until uniform. The magnesium stearate is then added with additional mixing and the product is filled into hard gelatin capsules.

What is claimed is:

1. The compound 1-acetyl-3-undecylpyrazole.

2. The compound 1-benzoyl-3-undecylpyrazole.

3. A compound having the formula R-( J=O in which R is a member of the group consisting of acetyl and benzoyl radicals.

4. A process for the preparation of a compound having the formula in which R is a member of the group consisting of acetyl and benzoyl radicals which comprises reacting n-lithio- S-undecylpyrazole with an acyl halide selected from the group consisting of acetyl halide and benzoyl halide.

References Cited in the file of this patent Shirley et al.: I. Am. Chem. Soc., vol. 75, pp. 375-378 (1953).

Kosuge et al.: Chem. Abstracts, vol. 49, col. 11628 (1955). 

3. A COMPOUND HAVING THE FORMULA 